Cognitive decline has a spectrum of presentations, which manifest from normality as part of senility to the established form of various neurodegenerative illnesses causing dementia. Understanding these various differential diagnoses is of great clinical significance as they have different management and interventional strategies. The neuropsychological deficits which are identified should follow known neuropathological disease patterns that helps in distinguishing different types of cognitive impairment to established dementia. It is important to look at different cognitive impairment in elderly with core diagnostic sense to define severity, type of cognitive impairments, identifying patients need for accommodation or adaptation, associated risks, effectiveness of therapies and predict mortality. This would help clinicians to identify and plan management based on individual needs in cases with variable cognitive impairment.

Cognitive decline is an inclusive term to describe any characteristic that acts as a barrier to the cognition process. A cognitive deficit, which includes learning and memory impairment, is one of the most prominent and debilitating consequence of normal and pathological aging in humans. Cognitive decline has a spectrum of presentations which manifest in normality as part of senility or senescence to the established form of various neurodegenerative illnesses causing dementia. A clinician must distinguish dementia from normal aging, age-associated cognitive impairment, mild cognitive impairment (MCI), drug-induced amnesia, cognitive decline due to chronic mental illness, delirium, aphasia and other focal cognitive syndromes.

Understanding these various differential diagnoses is of great clinical significance as they have different management and interventional strategies. Once dementia is recognized, the next step is the identification of the etiology. This requires a series of assessments including detailed history, mental status examinations, laboratory tests, physical and neurological tests along with neuroimaging of the brain, etc.

An approach to the differential diagnosis of cognitive decline is presented in this chapter which includes from the stage of senility to severe neurodegenerative illnesses.

Differential diagnosis of cognitive decline in elderly

Cognitive decline as "senility or senescence"

Differentiation of dementia from normal age-related cognitive changes in nonimpaired elderly is very difficult. [1],[2] This can be is seen even in highly educated healthiest elderly. [3],[4] The age-related cognitive changes are not to be generalized as they are quite variable. These usually do not cause significant dysfunctions and persons continue with their productive life. Based on broad geriatric evaluation, an association between functional alterations of senescence and disorders of gait and balance has been found. [5] "Bradyphrenia" was the term referred for slowing of mental processing, sensory inputs, and motor response. [1],[6] There is mild delay in recall due to decrease in retrieval of information with relative preservation of memory storage and procedural memory. [7],[8],[9] Moreover, some declines are notedin various areas offunctioning like working memory, executive functioning, and visuospatial skills. On the other hand, language functions are spared. Vocabulary remains preserved till late and narrative style becomes more complex. [10] There is enough research in areas of classical aging patterns including variability in presentation, neurophysiological changes, neuropathological changes, neuropsychological tests and neuroimaging findings. Normal aging results in change in the characteristic cognitive and behavioral pattern such as 0 under arousal and decreased processing of sensory apparatus, persistence of stimulus memory, impairment of higher mental functions, which includes decreased sustained attention, preserved crystallized Intelligence, but decreased fluid intelligence; progressive decline in performance intelligence quotient (IQ), but stable verbal IQ; richer narrative style and decreased active naming, decreased primary and working memory, decreased retrieval of stored memory, decreased perception, and increased spatial segmentation. However, overall, the cognitive changes with normal aging are not sufficient to interfere with activities of daily living. [11] Neurophysiological studies have shown change in sleep pattern, e.g., increase in sleep fragmentation, decrease in deep sleep and rapid eye movement sleep, and increase in daytime somnolence. Electrophysiological studies has shown shift of alpha wave frequency to lower range and increase in evoked response latency. [11] Neuroimaging studies have shown diffuse cerebral atrophy, mild enlargement of ventricular system, although, less than seen in cases of Alzheimer disease (AD), and tissue loss in prefrontal cortex, particularly the white matter. Studies have also shown decline in integrity of selective thalamic nuclei and projections with advancing age, particularly those in thalamofrontal, thalamoparietal, and thalamolimbic networks. [12] Neuropathological studies have shown that numerous degenerative chances as cerebral amyloid angiopathy are also found in around 3/4 th of cognitively normal and relatively well-educated individuals. [13] On neuropsychological tests, there is decline reported in speed dependent performance IQ. One of the most important change is noted in intelligence, i.e., predominance shift from "fluidic" intelligence (e.g., novel solutions) to "crystallized" intelligence (e.g., old solutions). [14]

The cognitive decline which is appropriate to age having variable presentation should not always be seen with labelling view for dementia rather it must be kept as one of the possibilities.

Age associated memory impairments

Age-associatedmemory impairments (AAMI) are seen when senility or senescence manifests with dysfunction. AAMI is defined on the basis of criteria first outlined by Crook etal., [15] which mentions that AAMI is a mild deficit in memory retrieval (poor recall which improves by recognition or cueing) in individuals with age more than 50 years. It has insidious onset of memory difficulty with impairment in daily functioning, standardized memory test score 1 or more standard deviation (SD) below the mean for young, scaled score of 9 or more on Wechsler adult intelligence scale, more than 23 on mini-mental state examination [16] and excluding specific medical and psychiatric cause for memory deficit. AAMI is usually a nonprogressive disorder but can be prelude to dementia. [17],[18] There are studies on understanding neurobiological basis and risk factor of AAMI which suggests age-related changes in temporal lobe structures, white matter and cholinergic system unlike apolipoprotein E å4 being risk factor for AD, [19] is not seen in AAMI. [20] Although the role of cognitive enhancers as a therapeutic interventions for AAMI have been studied but found to be minimally effective. [21]

Mild cognitive impairment

MCI is a stage of transition between 'normal' functional ability and a full-blown clinical picture of dementia. The term MCI refers to some lowering of cognitive function, from a formerly normal level toward a mildly impaired level. It exists across a cognitive continuum with borders that are difficult to define precisely. The operational criteria had been defined to counter the ambiguities which include: Complaint of defective memory, normal general cognitive functions, memory impaired for age (e.g., standardized memory test score 1.5 SDs or more below the mean for education and age-adjusted scores), absence of other evidence for dementia and excluding specific medical and psychiatric causes for memory difficulty. [22] There are mainly four subtypes of MCI, including AAMI, age-associated cognitive decline, amnestic MCI and cognitive impairment, not dementia. These have contributed to our understanding of MCI. [23]

Many different underlying reasons and etiologies may lead to this decline, including not only AD but also vascular lesions, alcohol abuse, epilepsy, depression, and others. Patients with AD pass through the MCI stage before presenting with AD dementia, but not all patients presenting with clinical MCI suffer from underlying AD pathology. [22] The prevalence of MCI in adults aged 65 years and older is 10-20%; risk increases with age and men appear to be at higher risk than women. [24] In older patients with MCI, clinicians should consider depression, polypharmacy, and uncontrolled cardiovascular risk factors, all of which may increase risk for cognitive impairment and other negative outcomes.

Although patients with MCI are at greater risk for developing dementia compared with the general population, there is currently substantial variation in risk estimates (from <5% to 20% annual conversion rates), depending on the population studied. Currently, no medications have proven effective for MCI; treatments and interventions should be aimed at reducing cardiovascular risk factors and prevention of stroke. [11] Aerobic exercise, mental activity, and social engagement may help decrease risk of further cognitive decline. Recently, the researchers have been in search for imaging biomarkers associated with cognitive decline. [25]

Amnesia

The difference between amnesia and dementia underlies the memory deficit as the only affected domain along with other cognitive abilities including attention remaining intact. The term "amnesia" is referred to clinically salient memory deficit which is more significant than MCI. There is marked inability to learn new information or recent events which are even not corrected by cues. Isolated amnesia is often misdiagnosed, rather over diagnosed as dementia. As the diagnosis of dementia requires two additional cognitive and behavioral domains, in such cases temporal correlation, serial observation, associated deficits, and behaviors must be identified, which gives clue for diagnosis of dementia. [11]

When memory loss is consistent as an isolated phenomenon, then it signifies an underlying focal lesions in the brain. There are lesions in following areas : b0 ilateral lesion in hippocampus, fornix, mammillary bodies or anteromedial nuclei of thalamus. Some amnestic syndromes are related to specific event or cause such as posttraumatic brain syndrome, cardiopulmonary cerebral resuscitation, drug toxicity, alcohol intoxication or thiamine deficiency leading to Wernicke's encephalopathy leading to Korsakoff's amnesia. Amnesia is also seen in case of dissociative disorder and can be differentiated by loss of identity and other information in presence of continued new learning.

Cognitive deficit in chronic mental illness

Cognitive psychology has become an important discipline in the research of a number of psychiatric disorders, ranging from severe psychotic illness such as schizophrenia to nonpsychotic illnesses, relatively benign, yet significantly disabling such as somatoform disorder. [26]

Although the range of cognitive problems can be diverse, there are several cognitive domains, including executive function (EF), attention and information processing, and working memory, which appear more frequently at risk.

Cognitive impairments in schizophrenia are not epiphenomena which means that they are not secondary to delusions, distracting effects of hallucinations, or gross motivational defects. [26] Cognitive impairments differ according to the clinical symptomatology, the deficits may be related more with disorganized and negative symptoms and less with psychotic symptoms. [27] There appears no pathognomonic neuropsychological profile in schizophrenia, likely due in part to etiological heterogeneity within the disorder. However, this has been the part of a debate as significant discrepancy lies with estimated premorbid levels of cognitive functioning along with severity of psychopathology as part of existing illness. [28] Based on neurodevelopmental theories of schizophrenia, in 22q11.2 deletion syndrome (22q11DS) early cognitive decline has been found to be a robust indicator for developing a psychotic illness subsequently. [29]

Cognitive deficits in major depression can mimic dementia. [30] In the acute phase of bipolar disorder, impairment of cognition may progress to a stuporous state. Cognitive deficits in mood disorders include impaired performance in tests of attention, EFs, and memory. Increased cognitive dysfunction is associated with greater severity of symptoms. Owing to the presence of cognitive deficits even during the euthymic states, it is suggested that certain cognitive deficits are fundamental trait characteristics. The relationships between mood and cognition are dynamic, with components that are trait dependent and others that are state dependent. [26] Decline in cognition has been attributed to reduced motivation, intrusive thought, impaired concentration, attenuated attentional capacity, and slowness. Cognitive deficits are more pronounced in melancholic than nonmelancholic depression. [31]

Delirium is an abrupt onset of cognitive decline characterized by fluctuating disturbances in attention. Delirium is the most common neurobehavioral disorder seen in general hospital setting. Like dementia, it is commonly seen in elderly patients. Around 10-24% of patients above 65 years age come to hospital in a delirious state,while the rest develop the same during the course of their hospitalization. [36],[37],[38] It is not uncommon to miss delirium from dementia particularly in advance stage or due to imbedded phenomenon. The symptom complex to elicit delirium in includes rapid onset, fluctuating course with lucid interval, disorientation, poor registration, perceptual disturbances, including hallucinations of any modality, sundowning, altered sleep-wake cycle and increased or decreased activity level, but among all the disturbance of attention is the cardinal symptom of delirium and cause of the disorientation and memory deficit. [38] During assessment, patient might give impression of faulty speech along with labeling of formal thought disorders. With regard to psychomotor component, the delirium can manifest as hypoactive type, hyperactive type, or as mixed type. Almost half of the delirious patients fall in last type, i.e., mixed type. [39]

On the basis ofcourse, temporality and phenomena, delirium can be differentiated from other Forms of cognitive decline. There can be various causative factors for delirium. Enlistingall can be exhaustive, but they can be grouped into four general categories: First, intoxication with exogenous substance including drugs, poisons or industrial agents; second, various systemic illnesses including infections, metabolic or endocrinopathies which Affect brain functioning; third, primary cerebral disease including infection, tumors, trauma, epilepsy and stroke; and fourth, as a part of complicated alcohol withdrawal. [11]

The common pathophysiology of the diverse causes of delirium syndrome is not entirely understood, but May involve metabolic susceptible polysynaptic pathways from ascending reticular formation of the thalamus, prefrontal cortex, posterior parietal cortex and associated focal lesion of latter sites mentioned. [40] There are various reasons for finding difficulty in making distinction between dementia and delirium among which the most logical is their coexistence or superimposed condition in elderly patients in later stages of dementia itself. Many systemic illnesses along with medications used to treat the illnesses, make elderly more vulnerable to such conditions. [41] Although the acute fatality rate is greater for delirium than for dementia, if the causative factor is corrected certainly delirium has better prognosis than dementia. Delirium which persists for more than 6 months, such as from chronic metabolic disorders, is a form of frontal-subcortical dementia. Furthermore, distinguishing delirium from different types of dementia may be difficult, e.g., dementia with Lewy bodies have similar fluctuations in their presentation.

Aphasia

Aphasia presents as focal cognitive deficit similar to amnesia. Altogether it can be mistaken for dementia particularly in fluent aphasia such as Wernicke's aphasia and transcortical sensory aphasia. Such patients manifest with empty verbal output with prominent paraphasic errors including word approximation or neologism. The major cognitive deficit is impairment in comprehension. Similar to amnesia, it can be seen as a part of progressive dementing disease like AD or may be an isolated finding due to focal lesions. The differential diagnosis of an isolated aphasia compared to dementia may be difficult because of heavy reliance of mental status examination on language. The disturbance of language interferes with testing various cognitive aspects like orientation, attention, memory, comprehension, abstraction, judgment etc., Which leads to difficulty in labeling phenomena definite for some diagnostic entities. Furthermore, when testable, nonverbal, or visual memory tests may demonstrate intact extralinguistic intellect. The examiner may have to rely upon general behavior and nonverbal findings to differentiate aphasia from dementia. [11]

Dementing diseases

Dementia is just not "senility" and much beyond. Between 3% and 5% of people aged over 65 have severe impairment of memory, intellect, orientation, and personality and a similar proportion have milder Form of dementia. [42] Dementia is not a diagnosis, but a syndrome whose etiology must be ascertained to recognize the reversible or modifiable causes. The alarmingconditions of intellectual impairment, whichdevelop when a person isover 60, are reviewed and the usefulness of investigations is assessed.

The two most important clinical aspects of assessment in an apparently demented person are, firstly, the onset and progression of the symptoms and secondly, the presence or absence of focal neurological symptoms and signs. Dementia is a chronic disorder developing over many months. "Acute dementia" resulting from profound cerebral anoxia is uncommon. [43]

Intellectual impairment which comes on insidiously and gradually worsens over months or years without any associated neurological features suggests several diagnostic possibilities. Dementing disease can be diagnosed by emphasizing on four major feature of the syndrome: Temporal, behavioral, cognitive and neurological features. Additional information with the help of selected laboratory tests and neuroimaging are effective in diagnosing majority of dementia syndrome with accuracy.

Temporal feature

This is the first step in elicitation of various differential diagnosis of cognitive decline as in dementing diseases. It is important to understand the onset and course of the disease in assessing its etiology. For example, slowly progressive illness with acute onset can be because of epilepsy, sub-acute onset can be due to neoplastic growth and gradual onset can be due to neurodegenerative dementias, Normal pressure hydrocephalus and inherited biochemical disorders. Creutzfeldt-Jakob disease More Details usually has sub-acute onset with rapid progression to death within months; posttraumatic dementia has acute onset, but remains static without progressive decline for subsequent duration; stair-step progression is seen in vascular dementia; and multiplerelapsesoccur in multiple sclerosis. Pseudodementia as part of depression typically has sub-acute onset and continues till patient responds to treatment for depression. [11]

Cognitive features

This is the second important feature to distinguish various dementing diseases. The differential pattern of neuropsychological deficit signifies involvement of different areas of the brain. There is variability in presentation which denotes that none of the dementing diseases involve whole of the brain equally rather it may be predominance of some part of brain and others may even bespared. Although dementing diseases cognitive profiles, most can be roughly divided into "cortical" and "frontal-subcortical" profiles. [11] Cortical dementias have cognitive changes primarily from involvement of cerebral association cortex and the mesotemporal limbic system, e.g., Alzheimer's disease, frontotemporal dementia (FTD) and asymmetric cortical atrophies. Frontal-subcortical dementias have cognitive changes primarily from involvement of related circuits that course down from frontal cortex through basal ganglia and thalamus and back to cortex. [44] Deficit in executive functioning is common in both cortical and frontal-subcortical types of dementia, but differs in cognitive characteristics. The cardinal feature of the mental status of patients with frontal-subcortical dementias is a slowing of cognition, mental processing, and speech. [44],[45]

Cortical dementia includes AD, FTD or Pick's complex and asymmetric cortical atrophies. It affects instrumental functioning, e.g., language, memory, praxis and complex visual processing. It resembles any focal lesions involving the cerebral cortex and includes aphasia with naming difficulty and impaired comprehension, memory disturbances, agnosia, and apraxia. Other deficits include visuospatial and constructional disturbances, calculating ability, etc. The tests to elicit cortical dementia include tests for naming, language comprehension, list learning and recall and constructions, which must be applied to detect cortical dysfunctions. Most of the other dementias involve frontal-subcortical circuits in white matter, basal ganglia and thalamus. Patients with vascular dementia and dementia with movement disorder have predominant frontal-subcortical features. [11]

The terms "cortical" and "sub-cortical" are not sufficient to distinguish the dementing disease. These are not pathologically absolute as in AD involvement of subcortical nucleus basalis of Meynert and its cholinergic projections occur and in vascular dementia there is involvement of cortical areas as well. Some dementias have mixed patterns like in toxic metabolic conditions or viral infections affecting both "cortical" and "sub-cortical" structures. Cortical dementia tends to have more of behavioral problems that reflect disease in association cortex. Anatomically and physiologically, the basal ganglia, selected nuclei of thalamus and prefrontal cortex form a unified frontal-subcortical system, and involvement of any of these affects the whole circuit. [45]

Behavioral features

This is the third distinguishing feature by which particularly FTD has been explained. The early behavioral changes like personality changes, loss of social and personal awareness, disinhibition, and compulsive and sociopathic acts, are not seen in most of the cortical dementias. Rather, the same have strong hold on frontal-subcortical dementias. [11] These behavioral changes may occur long before developing any memory or other cognitive deficits. There are other dementing diseases in which behavioral changes are not seen in the early course of the illness early course like most neurodegenerative dementias, Alzheimer's disease, asymmetric cortical atrophies, normal pressure hydrocephalus and inherited biochemical disorders.

Neurological features

All the above mentioned features must be assessed and interpreted in the context of neurological findings. A mandatory neurological examination gives a clue for possible etiology of the disease.

In many of the cortical dementias, the basic neurological examinations are found to be normal until the late phase of disease. In contrast, the frontal-subcortical dementias have many of the neurological deficits like abnormalities on motor examination, gait disturbances or other movement disorders. Frontal-subcortical circuits are affected by extrapyramidal disorders, hydrocephalus, white matter disease and subcortical vascular disease that produce maximal dysfunction in basal ganglia, thalamus and brain stem, and is usually accompanied by rigidity, tremors, and bradykinesia. A few common frontal-subcortical dementias are like Lewy bodies dementia, progressive supranuclear palsy, Huntington's disease and others. [46],[47],[48] A Lewy body is associated with dementia presenting with Parkinsonism More Details, attention deficit, and frequent visual hallucinations. Progressive supranuclear palsy resembles Parkinson's disease, but additionally has characteristic gaze palsy that presents with inability to look down voluntarily, prominent axial rigidity and extended neck, stiff and broad-based gait and dementia. Normal pressure hydrocephalus includes triad of dementia, gait disturbances and urinary incontinence which may respond to cerebro-spinal fluid shunting. [49]

This approach can lead to identification of most of the causes of cognitive decline in elderly presenting with deterioration. Detailed clinical assessment aided by laboratory studies like blood investigations, cerebrospinal fluid studies including cytological studies, serological studies, urinalysis and genetic studies for familiar AD, HD etc., and neuro-imaging investigations such as magetic resonance imaging, positron-emission tomography, magnetic resonance angiography and radioisotope cisternography, can help in clinching the exact nature and etiology of cognitive decline. [11]

In summary, various differentials for cognitive decline based on mental status assessment are as follows : 0 The possibility of delirium and dementia is suspected whenever impairment is in three or more spheres of cognitive functioning, and then based on case details like acute onset, attention deficit and fluctuating course, delirium can be differentiated. When impairment seen with relatively isolated memory deficit, the possibility of AAMI and MCI can be kept, which can be further assessed by specific tests having <1.0 SD for 20 years for AAMI and if <1.5 SD for age matched for MCI. When there is evidence of focal neurological disorder associated with 1 or 2 spheres of cognitive dysfunction then possibilities of aphasia, agnosia and apraxia should be considered.

Summary

Cognitive decline is a spectrum concept which manifests from age-associated normality to various neurodegenerative dementing illnesses. Based on clinical and formal assessment, it is not uncommon to see varied cognitive functions even in normal individuals. There is an approach to identify specific types of cognitive decline in elderly [Figure 1]. It is worth noting that the neuropsychological deficits that are identified follow a known neuropathological disease pattern which helps in distinguishing different types of cognitive impairment to established dementia. The neuropsychological deficits also vary between different types of dementias like AD has more profound memory deficits than FTD and within a dementia syndrome, considerable inter-individual variability might be noted, e.g., one patient with AD may exhibit more language dysfunction, while another may exhibit more visuospatial deficits. However, it is important to look at different types of cognitive impairment in elderly with core diagnostic sense to define severity, type of cognitive impairment, identifying patients need for accommodation or adaptation, associated risks, effectiveness of therapies and predict mortality. This can help clinicians identify and plan management based on individual needs in cases with variable cognitive impairment.

Figure 1: Systematic approach to differentiate various types of cognitive decline in elderly